PROJECT SUMMARY Cerebral palsy is the most common physical disability of childhood. Pediatric hemiplegia represents a third of this population and is often due to a unilateral brain injury that occurs in the prenatal or perinatal periods. Our recent work provides evidence that the timing of the injury has a significant effect on severity and type of motor impairment. If the brain injury occurs before birth, in which pruning of the ipsilateral corticospinal projections has not yet occurred, there is a relative preservation of these projections and strength in the paretic limb, however, this comes at the cost of abnormal mirror limb movements that are simultaneously driven from the contralesional hemisphere. Conversely, a later injury, in which pruning of the contralesional ipsilateral corticospinal projections is already occurring, there is a better likelihood for independent limb control, but this comes at the cost of increased expression of weakness in the paretic limb. Since time-varying interruptions can occur during developmental synaptic pruning, it is likely that white and gray matter complexity are concurrently altered to ultimately drive the expression of these specific motor impairments. The proposed project will provide unique insight into the plastic and degenerative neural microstructural mechanisms as a function of time in disrupted development as it relates to typical childhood development. There have been many diffusion tensor imaging studies of cerebral palsy, but there is no clear consensus on the neuropathophysiology primarily due to the inherent limitations in modeling capabilities, data acquisition, and heterogeneity of motor impairment expression in cerebral palsy. As an alternative, our laboratory specializes in practical techniques that go beyond the capabilities of diffusion tensor imaging to characterize white and gray matter neural complexity with advanced diffusion methods and modeling. Furthermore, as we are able to recruit individuals with heterogeneous sub- types of cerebral palsy through an extensive research registry, the proposed project offers, for the first time, to characterize the effects of injury timing on neural microstructural complexity and motor impairments in pediatric hemiplegia. Our central hypothesis is that timing of unilateral ischemic brain injury impacts neural tissue microstructural complexity in both hemispheres to cascade to motor impairments of hand weakness and stereotypic losses of independent upper limb control. Aim 1 is designed to provide novel imaging biomarker candidates of white and gray matter as a function of injury timing in neural development. Aim 2 is set up to quantify upper limb mirror movement and weakness using practical, yet novel, quantitative bedside device measures and clinical assessments. Preliminary findings of the proposed work will provide novel baseline biomarkers to guide future large scale (R01) basic science studies which are able to detect and study white and gray matter microstructural complexity for specific motor impairments in individuals with cerebral palsy.